CAMBRIDGE, Mass.—At the beginning of January, Atlas Venture announced the official launch of Generation Bio, a company focused on developing the first genetic medicines that can be titrated to effect and re-dosed for a lifetime of benefit. Atlas first founded the company in 2016 with a $25 million Series A financing round.

Since its founding in 2016, Generation Bio has reportedly demonstrated durable, dose-dependent expression and the ability to increase expression in the liver with re-dosing in vivo with its GeneWave platform. The company is initially focused on developing medicines for rare genetic diseases, including inherited metabolic disorders and lysosomal storage diseases, as well as emerging treatment areas where large numbers of patients cannot be addressed by current gene therapy modalities. Beyond the liver, the company has also demonstrated durable in-vivo expression in muscle, the retina and the central nervous system.

Rare disease leader Dr. Geoffrey McDonough has been named as president and CEO of Generation Bio. Previously, McDonough was CEO of Swedish Orphan Biovitrum (Sobi), and before that served as Genzyme’s president EMEA and as general manager of the lysosomal storage disease franchise at Genzyme.

“Geoff McDonough is a visionary leader with deep experience guiding rare disease-focused companies, and we are thrilled to have him on board as CEO of Generation Bio,” says Jason Rhodes, a partner at Atlas Venture and a founder and chairman of Generation Bio’s board of directors. Rhodes notes that in leading Sobi, McDonough helped the company become a prominent rare disease biotech company with a robust commercial portfolio, and that he brings deep commercial and clinical experience “that will prove invaluable as Generation Bio develops its breakthrough technology platform into a suite of therapeutic applications.”

McDonough tells DDNews, “We are creating the first genetic medicines with drug-like properties. Our GeneWave technology has multiple attributes that distinguish it from both existing gene therapies and those currently in development. It is capsid-free, allowing it to avoid the immunogenicity and background immunity that limits viral vector-based approaches. GeneWave’s lack of immunogenicity and the corresponding ability to re-dose significantly expands patient access.

“The ability to titrate and re-dose gene therapies is extremely important. Gene therapies today cannot be delivered to young children, as their livers continue to grow until early adolescence, diluting the effect of the transgene. GeneWave enables early therapeutic intervention as well as re-dosing during this period of hepatic growth in order to have the greatest possible impact on genetic diseases over a patient’s lifetime.”

He also explains that GeneWave allows the ability to—via titration—choose a low starting dose and incrementally re-dose each patient until they reach the desired level of gene expression, just like a traditional medicine with pharmacological properties.

“GeneWave can deliver larger transgenes compared with recombinant AAV approaches, widening the landscape of therapeutic applications for gene therapy. Another aspect of this larger capacity is the potential to deliver more than one gene to address more complex diseases. This is an unprecedented capability,” McDonough continues.

The company’s core technology was discovered by Generation Bio scientific founder and head of discovery, Dr. Robert Kotin. As a senior investigator at the National Institutes of Health, Kotin discovered a novel modality for non-viral gene transfer known as closed-ended DNA, or ceDNA. This eukaryotic DNA has a unique ability to translocate from the cytoplasm of the cell to the nucleus without the use of a viral capsid. Once in the nucleus, ceDNA forms stable, non-integrating episomes that result in high levels of long-term gene expression. The technology can also accommodate much larger genes and regulatory elements, allowing for a greater number of diseases to be addressed.

According to Rhodes, “Generation Bio is pioneering a completely novel modality of gene therapy by creating the first genetic medicines that can be titrated to a target level of expression in each patient, and then re-dosed later in life if necessary. The company’s GeneWave technology has the potential to achieve what no other gene therapies have yet done—deliver genetic medicines with truly drug-like properties and scale. We believe GeneWave will transform treatment paradigms across a range of genetic diseases. Atlas has a long track record of creating major new therapeutic modality companies such as Alnylam and Intellia.”

“Our GeneWave platform, the first therapeutic application of ceDNA, uses a state-of-the-art lipid nanoparticle (LNP) to intravenously deliver ceDNA to the liver, where it may be used to either address diseases of the liver itself or to transform the liver into a living ‘biofactory’ for expressing secreted proteins to treat a wide variety of genetic diseases,” McDonough says. “Using this approach, we have already demonstrated in-vivo re-dosing and durable expression in preclinical models.”

He adds that the company is initially focused on developing medicines for rare genetic diseases, with intrinsic diseases of the liver—such as progressive familial intrahepatic cholestasis, phenylketonuria and glycogen storage disease 1a—among the candidates Generation Bio is exploring. Using the liver as a biofactory can be applied to multiple rare genetic diseases, such as lysosomal storage diseases and hemophilia, McDonough says, adding: “Our technology has demonstrated in-vivo durability of expression in multiple tissues, including the eye, the central nervous system and muscle tissue. Potential future areas of application include genetic lung disease, genetic eye disease and genetic nervous system disease, and our technology may also address key issues in gene editing for clinical applications.”

“We are working towards declaring two liver-directed GeneWave development candidates in the next 18 months based on completing additional preclinical work in relevant disease models in mice and in NHPs [non-human primates], and to subsequently move these development candidates into IND-enabling studies,” McDonough notes. “We are also working on optimizing ceDNA for delivery to other key tissues such as the lung, retina, CNS [central nervous system] and muscle.”

“Generation Bio has the potential to bring the benefits of gene therapy to a much wider population of patients with rare diseases than are eligible for treatment today. Even more exciting is the potential to address monogenic diseases with genes too large to be targeted, and to develop the potential to deliver more than one gene to treat more complex diseases. Finally, the production scale for the GeneWave platform is sufficient to bring significantly larger diseases into reach for genetic medicines for the first time,” McDonough concludes.